Inhaler

ABSTRACT

An inhaler for dispensing droplets of liquid medicament to a patient comprising a body having a mouthpiece or nasal adaptor and a reservoir of liquid medicament in communication with an aerosol generator. The aerosol generator includes a chamber for the liquid medicament and a nozzle arrangement having a plurality of orifices. Means are provided for cyclically pressurizing the liquid medicament in the chamber such that liquid from the chamber is periodically expelled through the orifices of the nozzle arrangement as atomizer droplets of liquid medicament. Dosage control means are also provided for deactivating the aerosol generator after a predetermined time or after a predetermined volume of liquid medicament has been expelled from the chamber.

FIELD OF THE INVENTION

This invention relates to inhalers for the delivery of therapeuticsubstances to the respiratory system of a patient and in particular toinhalers which deliver the therapeutic substance in the form of a liquidas a dispersion of fine droplets.

BACKGROUND

Since the metered dose pressurised inhaler was introduced in themid-1950's, inhalation has become the most widely used route fordelivering bronchodilators, offering a rapid onset of action and a lowinstance of systemic side effects. More recently, inhalation from apressurised inhaler has been a route selected for the administration ofother drugs, e.g., ergotamine, which are not primarily concerned withthe treatment of a bronchial malady.

The metered dose inhaler is dependent upon the propulsive force of apropellant system used in its manufacture. The propellant generallycomprises a mixture of liquified chlorofluorocarbons (CFC's) which areselected to provide the desired vapour pressure and stability of theformulation. Propellants 11, 12 and 114 are the most widely usedpropellants in aerosol formulations for inhalation administration.

In recent years it has been established that CFC's react with the ozonelayer around the earth and contribute towards its depletion. There hasbeen considerable pressure around the world to reduce substantially theuse of CFC's, and various Governments have banned the "non-essential"use of CFC's. Such "non-essential" uses include the use of CFC's asrefrigerants and blowing agents, but heretofore the use of CFC's inmedicines, which contributes to less than 1% of the total use of CFC's,has not been restricted. Nevertheless, in view of the adverse effect ofCFC's on the ozone layer it is desirable to seek alternative propellantsystems which are suitable for use in inhalation aerosols or an inhalerwhich is capable of delivering drugs in such an efficacious mannerwithout employing an aerosol propellant.

Apparatus for atomising liquid, such as, liquid fuel, water, liquid drugand recording medium are disclosed, for example, in U.S. Pat. Nos.3,812,854, 4,159,803, 4,300,546, 4,334,531, 4,465,234, 4,632,311,4,338,576 and 4,850,534 and International Patent Application No.WO/8906147.

The atomising apparatus disclosed in U.S. Pat. Nos. 4,465,234 and4,632,311 comprises a body having a chamber into which liquid issupplied, a nozzle member secured to the body and forming part of a walldefining the chamber, the nozzle member having at least one nozzleopening therethrough, and vibrator which is either a separate elementforming part of a wall defining the chamber or is secured to the nozzlemember to cause vibration thereof, such that, in use, in response to thevibrator, liquid in the chamber is cyclically pressurised, causingliquid to be periodically expelled through the nozzle opening(s) asatomised droplets. The apparatus additionally comprises a reservoir ofliquid positioned below the chamber and a suction pump in communicationwith the chamber via an air vent pipe for sucking liquid into thechamber. The pump is de-energised after operation to drain liquid toleave the chamber dry during non-working periods to prevent theotherwise solid substances from clogging the nozzle openings.

U.S. Pat. No. 4,533,082 discloses an arrangement for discharging liquiddroplets which is useful in applications such as fuel burners andprinters, the arrangement comprises a housing including a chamber forholding liquid therein having an intake port connected to a liquidsupply container, a vibrating member secured to the housing in pressuretransmitting relation with the liquid in the chamber. The vibratingmember is formed with at least one nozzle opening therein through whichthe liquid is discharged forwardly of the housing. A piezo-electrictransducer is secured to the vibrating member for inducing a rearwarddisplacement therein to discharge a small quantity of liquid through thenozzle opening.

U.S. Pat. Nos. 4,338,576 and 4,850,534 disclose a nebuliser which pumpsup water and mists the pumped up water comprising an elongated main bodywith a centre hole for water passage, and piezoelectric vibrationelements together with electrodes for energising the same mounted on themain body. The vibration elements are water-proofed, with the nebuliseritself supported by a flange on a water-proof member, which flange is ona plane on which a centre electrode is positioned. Upon vibration of theelements, water is pumped up through the inlet of the main body anddissipated into the air through the outlet of the main body. Preferably,the inlet and the outlet are removable from the main body and the inletcoated with a thin hard film. The outlet is preferably covered with amesh, or at least an opening of the outlet is covered, for preventingthe release of water that has not been converted to mist.

British Patent Application No. 2240494A, published 7th Aug., 1991,discloses a dispensing apparatus comprising a housing defining a chamberreceiving in use a quantity of liquid to be dispensed, the housingcomprising a perforate membrane which defines a front wall of thechamber and which has a rear face contacted by liquid in use, theapparatus further comprising vibrating means connected to the housingand operable to vibrate the perforate membrane to dispense droplets ofliquid through the perforate membrane, wherein the housing comprises anannular member having a relatively thin inner annular portion connectedto the perforate membrane and a relatively thick outer annular portionconnected to the vibrating means.

SUMMARY OF THE INVENTION

The present invention provides an inhaler capable of dispensing doses ofa liquid medicament in the form of atomised droplets.

According to the present invention there is provided an inhaler devicefor dispensing droplets of liquid medicament to a patient comprising abody having a mouth piece or nasal adaptor, and a reservoir of liquidmedicament in communication with an aerosol generator, the aerosolgenerator comprising a chamber for liquid medicament and a nozzlearrangement comprising a plurality of orifices in fluid flowrelationship with liquid medicament in said chamber, means forcyclically pressurising the liquid medicament in said chamber such thatliquid from said chamber is periodically expelled through the orificesas atomised droplets of liquid medicament so they may be inhaled via themouth piece or nasal adaptor, the inhaler additionally comprising dosagecontrol means for deactivating the aerosol generator after apredetermined time or after a predetermined volume of liquid medicamenthas been expelled from the chamber.

The inhaler of the invention is capable of dispensing accurate doses ofliquid medicament in the form of atomised droplets of size suitable forinhalation therapy. The inhaler may be constructed in the form of asmall battery powered, portable device, e.g., pocket sized, capable ofbeing used to dispense metered doses of liquid drugs, as a replacementfor conventional pressurised aerosol inhalers. The term "liquid drugs"includes drugs in solution form, e.g., in aqueous solution, ethanolicsolution, aqueous/ethanolic mixture solution, etc. and in colloidalsuspension form.

In a preferred embodiment of the invention the inhaler comprises meansto detect a patient's inspiration associated with a triggering means inorder that the inhaler may be automatically triggered at the correctpoint of a patient's breathing cycle thereby avoiding the need for thepatient to co-ordinate inspiration with operation of the inhaler.

The aerosol generator used in the inhaler of the invention comprises achamber for liquid medicament and a nozzle arrangement comprising aplurality of orifices in fluid flow relationship with the liquid in thechamber. The orifices typically have a maximum opening in the range 2 to50 μm (microns) and produce atomised droplets having a size comparableto the diameter. For medicament intended to reach the alveoli of thelungs, the apertures desirably have a maximum opening of from 2 to 10 μm(microns), preferably below 5 μm (microns), in order to produce atomiseddroplets within that range. For liquid medicament intended to beadministered to the nasal passage, mouth, throat or other parts of therespiratory system, the larger orifices may be employed. The orificesmay have the same or different diameters. Preferably, the orifices aretapered towards the intended outlet for the liquid. The orifices aregenerally spaced from each other by distances within the range 20 to 200microns. The nozzles may be fabricated by the same technique tomanufacture microsieves, e.g., electro forming in nickel. Alternatively,the nozzle arrangement may be formed by patterned anisotropic etchingthrough a thin semiconductor wafer, e.g., of silicon or germanium.Alternatively, plastics nozzle arrays may be used.

The thickness of the nozzle arrangement is typically in the range 20 to100 μm (microns).

A preferred nozzle array comprises an electroformed nickel foil about 10μm thick with holes approximately 6 μm in diameter set on a 50 μm pitch.A reinforcing grid of about 60 μm thickness is electroformed over thethinner foil for additional strength. Such foils are commerciallyavailable from Stork-Veco BV of Holland and have been sold for use asmicrosieves.

The aerosol generator is constructed to cyclically pressurise liquid inthe chamber causing the liquid periodically to be expelled through theorifices as atomised droplets of liquid. The cyclic pressurisation maybe achieved utilising a piezo-electric element which is caused tovibrate ultrasonically and acts directly or indirectly on the liquid.

In one embodiment of the invention the chamber of the aerosol generatorcomprises a flexible disc forming or in contact with at least part of awall of the chamber, the flexible disc being attached to a piezoelectricelement, to form a vibrator element. The vibrator element is excited bya suitable resonant frequency typically in the ultrasonic range of 50 to250 kHz, although the range 10 kHz to 500 kHz may be employed.Ultrasonic pressure waves propagate through the disc, cavity walls andliquid, resulting in liquid being forced periodically at ultrasonicfrequencies through the nozzles. The use of a resonant mode above thefundamental mode frequency enables low drive voltages and power toachieve high liquid ejection flow rates through the nozzle arrangement.The flexible vibrator element may conveniently be positioned in a wallopposite to the nozzle arrangement, although this configuration is notessential and the vibrator element may be in any position which willpropogate a pressure wave within the liquid causing droplets to beexpelled through the nozzle arrangement.

Suitable vibrator elements are commercially available from Kyocera andMurata of Japan and have been sold for use as piezo acoustic buzzerelements. The elements are brass 20 mm in diameter bonded to a 14 mmdiameter piezo electric disc. The brass disc may be polished andelectroplated with nickel to give a corrosion resistant finish.

The material forming the remaining cavity walls of the aerosol generatorhas been found to give best results if it is a relatively low acousticloss and impedance material. For example, aluminium alloy, Perspex,polycarbonate and ABS plastic have been found to work well, whereasnickel and stainless steel are not so effective.

One advantage of ABS is that it may be injection moulded to form acomplete assembly. In this case the aerosol generator disc may be linkedto the body of the device by a `limb` which contains the liquid feedchannel.

The adhesive bonding between the vibrator element and the cavity wallsis also important. Two part epoxy resins, e.g., Araldite commerciallyavailable from Ciba-Geigy in the United Kingdom, work well whereassilicone rubber does not, suggesting that good acoustic coupling betweenthe components is desirable. The nozzle array may also be convenientlybonded with epoxy resin. Hot melt adhesives may also be employed.

In an alternative embodiment of the invention the nozzle assembly isvibrated. The nozzle assembly may be flexible and comprise apiezo-electric element, e.g., in the form of a ring attached to thenozzle array extended around the orifices, such that when thepiezo-electric element is excited it causes vibration of the nozzlearrangement at ultrasonic frequencies resulting in cyclic pressurisationof the liquid in the chamber and ejection of droplets of liquid throughthe orifices.

In a preferred embodiment the nozzle assembly is vibrated by a vibratorelement comprising a piezo-electric ring secured to a metal disc oflarger diameter, the vibrating element having a central aperture throughwhich droplets from the nozzle array are emitted. The vibrating elementis preferably secured only over its central portion, either directly tothe nozzle array or to the housing of the chamber in close proximity tothe nozzle array e.g. over a central portion of about 4 mm diameter,such that ultrasonic energy is transferred directly to the nozzle array.This arrangement allows the outer area of the vibrating element, whichis typically about 20 mm diameter, to vibrate freely as a resonator andenables aerosol generation to occur with an input power to thepiezo-electric element of about 0.5 W. Also the arrangement has lesstendency to draw tiny air bubbles in through the nozzles duringoperation, since this reduces the tendency for and effects of,vibrational mode hopping which can occur if the piezo driver is attachedaround its periphery.

The drive frequency for this arrangement is still typically in the range250 to 400 kHz where the vibrating element operates in an overtone modewith a complex mode pattern. It is likely that this frequencycorresponds to the radial mode of the piezo which in turn excites othermodes in the metal element. The use of overtone frequencies of the metalelement i.e. those above the fundamental allows thin, low cost pieces ofpiezo to be employed. Generally, the thickness of the piezo element andthe metal disc should be similar. Hence if the metal thickness wereincreased to raise the fundamental resonant frequency of the vibratingelement a thicker piezo element, and therefore of higher cost, wouldalso be required.

The overall dimension of the aerosol generator may be small, e.g., 20millimeters in diameter and 3 millimeters thick and is capable ofdelivering volumes of several microliters of atomised droplets of liquidin a time period of about 0.5 seconds.

The chamber of the aerosol generator is supplied with liquid medicamentfrom a reservoir. It has been found that the presence of air in thechamber or liquid, even in the form of minute bubbles may deleteriouslyeffect the performance of the aerosol generator, particularly if airbubbles are present in the region of the nozzle arrangement. This effectis less marked with the arrangement where the vibrator element isattached directly to the nozzle array or to the housing in closeproximity to the nozzle array. The reservoir may be arranged to supplyliquid to the chamber only when the inhaler is used, although inpractice it has been found that it is difficult to repeatedly fill andempty the chamber of the aerosol generator without entrapping airbubbles during the filling. Accordingly, it is preferred that thechamber is permanently filled with liquid. In order to avoid the problemof liquid leaking from the chamber via the nozzle arrangement during thetime when the inhaler is not in use, e.g., storage in a pocket, thenozzle arrangement may be conveniently sealed with a cap.

Also, it is desirable for the reservoir to supply the chamber at aslight negative head of pressure regardless of the reservoirorientation. This effect may be achieved by employing a liquid reservoirin the form of a collapsible bag or sachet having a feed tube connectingwith the chamber sealed within the bag. The bag may conveniently beconstructed of latex rubber, polyester or other polymer materials orcomposite materials such as a metalised polymer laminate. The structureof the bag or sachet is such that it has some stiffness giving atendency to expand to a state of maximum internal volume. This may beaccomplished by the natural stiffness of the bag walls, by internalexpansion means, e.g., a spring or compressed foam insert within the bagor by positioning the bag in a container containing a gas at a pressureless than atmospheric pressure. The container may be conveniently in theform of a metal can or other impermeable material which will also serveto reduce evaporation losses of liquid. The container may be vented toatmosphere periodically in use to prevent an excessive negative pressurefrom building up in the reservoir as the liquid is dispensed.

The inhaler device of the invention additionally comprises dosagecontrol means such that the inhaler will be deactivated after apredetermined time or after a predetermined volume of liquid has beendispensed. The dosage control means preferably comprises means formeasuring the volume of liquid supplied to the chamber and means togenerate a signal after a predetermined volume of liquid has beensupplied, which signal is used to deactivate the aerosol generator.Alternatively, the dosage control may comprise a timer which allowsactuation of the aerosol generator for a predetermined period andthereafter causes deactivation.

The dosage control means may conveniently be positioned to measure thevolume of liquid passing through a section of a conduit connecting thechamber of the aerosol generator to the reservoir. In one embodiment ofthe invention the dosage control means comprises a length of tube insidewhich a close fitting, free moving slug is located. The net density ofthe slug is approximately matched to that of the liquid which flowsthrough the bore of the tube, i.e. the slug has neutral buoyancy. Theposition of the slug inside the tube is monitored by optical,electrical, magnetic, capacitive or electromagnetic or other such means.At the start and/or end of the liquid dose measurement period the slugis set to a predetermined or measured position, for example, by means ofa push-rod or another slug or by magnetic attraction pushing or pullingthe slug itself against an end stop. The aerosol generator is thenactivated and liquid is drawn through the gauge. As the liquid movesalong the gauge, the slug is drawn along with it until it reaches apredetermined end point whereupon the aerosol generator is de-activatedand the liquid flow stops. The slug may then be reset to its startposition by the means described previously. The clearance between theslug and the tube bore is such that the slug both moves along with theliquid flow and may be reset in position by an external force with nonet liquid flow as the liquid may flow around the slug as it is returnedto its starting position. The liquid gauge may be modified to give acontinuous reading of volume dispensed as well as providing a dosecompleted output by continuously detecting the position of the slug.Examples of such liquid gauges are disclosed in our copending BritishPatent Application No. 9027256.8.

Bubbles inside the system can present a very serious problem since theycan prevent operation of the aerosol generator and/or dose gauge. Hencethe bubble free filling and maintenance of a bubble free system is ofparamount importance. To reduce the effects of the liquid outgassing toform bubbles during the service life of the device a portion of theliquid feed system may be formed with a gas remover. An area of somepart of the liquid feed system is made from microporous material,capable of allowing the passage of gas but not of liquids. Suchmaterials are commercially available, e.g., from 3M, and are typicallypolymers such as polypropylene or high density polyethylene containing anetwork of pores of typical diameter<1 μm. The area of such material incontact with the liquid is generally at a point along the feed tubingbetween the reservoir and aerosol generator. It may even be part of thewall of the feed tubing. On the other side of the microporous materialto the drug solution is a sealed space with an internal vacuum orreduced air pressure. The gas remover works by simply causing any smallair bubbles to pass through the microporous membrane material into theregion of vacuum or low pressure, thus allowing a supply of liquid tothe cavity without the risk of air bubble incorporation. This provides apositive means of removing air bubbles before they can reach thedelivery cavity of such a device and upset its operation. This providesan extra degree of insurance against such air bubble originated problemsunder all operating conditions. Because the hydraulic pressures in theliquid feed system are unaltered by the presence of this gas remover andremain constant, then the operation of the device is not compromised inany way. The capacity of the gas remover can be chosen for any desiredlevel of bubble removal ability, completely independently of thereservoir, feed system and cavity volumes.

Air bubbles may enter the aerosol generator through the orifices of thenozzle arrangement when the device is not in use. Subsequent operationof the device does not always dislodge such air bubbles and maydeleteriously affect the performance. Accordingly, the device preferablyincludes a cover or cap to seal the nozzle arrangement to prevent theingress of air when the device is not in use. In a preferred embodimentthe cover has a self-closing action which seals the nozzle arrangementwhen the patient ceases to inspire through the mouthpiece after deliveryof a dose of medicament or when the device is released by the patient.The self-closing action may be achieved by mechanical, e.g., spring,electromechanical, pneumatic or hydraulic means. Our copending BritishPatent Application No. 9027255.0 "Closure system for inhalers" disclosessuitable cover systems for use in the invention.

In addition, or as an alternative, the cover for the nozzle arrangementmay be provided with a gas permeable membrane which can be sealedagainst the nozzle array outer surface and may have a partial vacuumgenerated by a manual pump, e.g., a rubber bulb, to remove any airbubbles from behind the nozzle arrangement.

The inhaler preferably includes a breath actuation sensor for detectinga patient's inspiration, which sensor provides a signal for actuatingthe aerosol generator. Thus, a patient simply breathes through the mouthpiece or nasal adaptor of the inhaler, the breath actuation sensor willdetect the patient's inspiration causing the aerosol generator to emitatomised droplets of liquid medicament which are entrained in thepatient's inspiratory air flow. The aerosol generator will bedeactivated by dosage control means as soon as the required dose ofmedicament has been dispensed. It is readily possible to dispenseeffective doses of liquid medicament during a single inhalation.

The breath actuation sensor may be a mechanical device, for example, apivoted vane, which moves to close a switch when there is an air flowthrough the mouth piece. Alternatively, the air flow may be detected bya flow transducer, pressure differential transducer or temperaturesensor which detects the cooling effect of an air flow, to provide asignal to trigger actuation of the aerosol generator. The breathactuation sensor may conveniently be positioned in a passage or chamberbetween an air inlet of the inhaler and the mouth piece or nasaladaptor. The breath actuation sensor may be associated with one or moreflap valves in order to prevent air flow over the sensor should thepatient exhale through the mouth piece or nasal adaptor.

The inhaler is preferably constructed such that when the patientbreathes through the mouthpiece air flowing through the inhaler and thedroplets emitted from the aerosol generator are thoroughly mixed as soonas possible after the droplets have left the nozzles if dropletcollisions and formation of large droplets are to be minimised. Thedroplets are emitted at around 10 m/s from each nozzle, and follow eachother along a droplet `streamline`. At an operating frequency of 150kHz, the axial spacing of the droplets is around 65 μm. If the dropletswere to be ejected into still air then the droplet streamlines wouldslow down and the droplets would all touch at around 1 to 2 m/s. Forthis inhaler application the droplet size is important to maximiseefficacy and hence collisions should be avoided. Therefore the dropletsare best injected into a fast moving air stream flowing at right anglesto the droplet ejection velocity. This may be achieved by siting thenozzle array at the constriction of a venturi with the air flowing overthe top of the nozzles. In this way the droplets may be rapidly andeffectively dispersed in the flowing air. Typical minimum air flowsrequired are from 20 to 30 liters/min. through a venturi which variesbetween 20 mm inlet and outlet diameters to a 10 mm constrictiondiameter over a few centimeters.

The complete inhaler system preferably comprises two main parts, areplaceable cartridge and a re-usable hand unit.

The replaceable cartridge contains the drug solution and all componentswhich come into contact with it i.e. liquid dose gauge, reservoirsachet, aerosol generator cavity, nozzle array etc. The nozzle cap maybe retained on the cartridge or may be present on the hand unit. Thecartridge is relatively low cost and disposable.

The re-usable hand unit accepts the cartridge and contains themechanical and electronic components necessary for generation. Forexample, the automatic capping system which comprises a small electricmotor and leadscrew driving the cap carrier, with associated opticalsensors to monitor the cap position and motor rotations may be retainedin the hand unit. The venturi to condition the airflow and mix it withthe droplets may also be retained in the hand unit with a thermistor tosense air flow rate at its intake. In addition, the hand unit containsone or more batteries to power the system together with the mainelectronics and switches.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIGS. 1a and 1b are block diagrams of an inhaler of the invention,

FIG. 2 is a cross-section diagram showing a liquid reservoir, suitablefor use in an inhaler of the invention,

FIG. 3 is a cross-section diagram showing a metered liquid dose gauge,suitable for use in an inhaler of the invention,

FIG. 4a is a cross-section diagram of an aerosol generator,

FIG. 4b is a front view of the aerosol generator of FIG. 4a,

FIG. 5a is a cross-section through a silicon nozzle array, suitable foruse in an inhaler of the invention,

FIG. 5b depicts a cross-section through an electro formed nickel nozzlearray, suitable for use in an inhaler of the invention,

FIGS. 6a and 6b are function block diagrams of electronic circuits formaintaining the vibrator element at a selected resonant frequency,

FIGS. 7a-7f show sample electronic circuits for the blocks of FIGS. 6aand 6b,

FIG. 8 depicts a cross-section through a breath actuation sensor,suitable for use in an inhaler of the invention,

FIG. 9 is a schematic diagram of a cross-section through a nozzle capand reservoir vent valve assembly, suitable for use in an inhaler of theinvention,

FIG. 10 is a function block diagram of a complete metered dose aerosoldelivery system, suitable for use in an inhaler of the invention,

FIG. 11 represents a schematic diagram of an inhaler in accordance withthe invention.

FIG. 12 represents an electromechanical capping system for the nozzlearrangement of an aerosol generator suitable for use in the invention,

FIG. 13 represents an optical liquid dose gauge suitable for use in theinvention,

FIGS. 14a-14c represent electronic circuits suitable to interface withthe dose gauge of FIG. 13,

FIGS. 15(a), 15(b) and 15(c) represent end, side and plan views of afurther inhaler in accordance with the invention,

FIGS. 16 and 17 represent diagrammatic plan and side views of areplaceable cartridge for use in the inhaler of FIG. 15,

FIG. 18 represents a diagram of the aerosol generator used in theinhaler of FIGS. 15 to 17,

FIG. 19 represents a diagram of the cap arrangement used in the inhalerof FIG. 15,

FIGS. 20(a) to 20(d) represents a diagram showing alternativeconfigurations of an aerosol generator having a replaceable cartridge,and

FIG. 21 represents a diagram of a magnetostrictive drive for use in aninhaler of the invention.

DETAILED DESCRIPTION

Referring to FIG. 1a, the drug delivery system comprises a liquidreservoir (1), flow gauge (2) and aerosol generator (3) linked by tubingor channels or other means allowing the controlled flow of liquidbetween (1), (2) and (3). The flow gauge (2) and aerosol generator (3)are also connected to electronics (4) providing the necessary drivevoltages and signal processing functions. A breath actuation sensor (5)is also linked to the electronics (4) and provides a trigger to start ametered dose delivery cycle. The liquid reservoir (1) and aerosolgenerator (3) are also provided with a vent valve and cap respectively,both of which are closed when the system is not in use. This system is aclosed loop controlled drug delivery system.

An alternative system configuration is shown in FIG. 1b, comprising aliquid reservoir (6), aerosol generation (7), electronics (8) and abreath sensor (9). In this case where no flow gauge is included thedelivered dose is controlled by the activation period of the aerosolgenerator alone and is therefore an open loop controlled drug deliverysystem.

The individual system components shown in FIGS. 1a and 1b will now bedescribed.

Referring to FIG. 2, a reservoir for storing the liquid to be ejectedwith minimal evaporation losses and supplying the liquid at the correctpressure to the other system components, comprises an impermeable, solidvessel (12) containing a collapsible bag (10) filled with liquid (16).The bag (10) is filled with liquid so as not to contain any gas bubblesby a method such as vacuum back filling. The bag (10) is sealed to afiller tube (14) by tying, bonding or other such means at point (22).The stiffness and geometry of the bag walls is such that the bag tendsto spring to a state of maximum internal volume, hence, as the liquid(16) is drawn from the reservoir then a negative differential pressurewith respect to atmosphere is created. The pressure is typically of theorder of a few centimeters head of water which is transmitted throughoutthe system and prevents seepage of liquid from the aerosol generatornozzles, whatever the orientation of the device. A piece of flexiblesoft tubing (20) in a material such as silicone rubber is attached tothe filler tube (14) inside the bag to prevent damage to the bag if thedevice is subject to mechanical shocks. It also ensures that the liquid(16) is drawn from the centre of the bag (10) reducing the possibilityof any unwanted bubbles incorporated due to imperfect filling beingcarried through the system. The vessel (12) also has a vent hole (18)which is linked to a valve at the end of the vent tube (24). This valveis opened to atmosphere when the device is in use to prevent anexcessive negative pressure from building up in the reservoir as theliquid (16) is drawn from the bag (10).

Referring to FIG. 3 a liquid dose gauge comprises a length of tubing(30) in a suitable material such as glass or plastic which contains afree moving slug (26) in a suitable material or composite of materialssuch as glass, plastic or metal. The slug (26) contains a small piece ofsteel wire, ferrite or other magnetic material (28) which is fixedwithin the slug and serves to enable the slug (26) to be magneticallyreset against an end stop (32) in the tube (30) when an end coil (34) isenergised with electrical current.

The net density of the slug (26) is matched to that of the liquid (16)such that the operation of the flow gauge is independent of the unitorientation and motion. The slug (26) is restrained axially within asection of the tube (30) by the two end stops (32) and (44). These endstops each contain a central aperture (42) and (46) which allows theliquid (16) to flow through the gauge. The position of the slug (26) ismonitored by an arrangement of three coils (34), (36) and (38) wound ona former (40), configured as a differential transformer. In this case,the central coil (36) is energised with an alternating current at afrequency of the order of 10 kHz. The mutual inductance between thecentral coil (36) and each of the outer coils (34) and (38) is dependenton the position of the magnetic material (28). If the coils (34) and(38) are connected in anti-phase then a null output is obtained when themagnetic material (28) is disposed symmetrically between the coils.Hence this is a convenient end point to detect for the travel of theslug (26) as the liquid (16) flows through the gauge. The generalconcept of the differential transformer is well known to those versed inthe art of measurement systems. From the above it may be seen that thecoil (34) and the magnetic material (28) perform dual functions, i.e.,that of resetting the slug (28) against end stop (32) and that ofenabling the detection of the end point. End point detection may also beachieved by using only a single coil (34), by monitoring the selfinductance of that coil alone which will depend on the position of themagnetic material (28) within it. Typical dimensions for such a gaugemay be approximately 10 mm in length with a tube bore of around 1 mm. Aclearance of approximately 0.1 mm around the slug is suitable.

Referring to FIGS. 4a and 4b, an aerosol generator comprises a disc ofmaterial (52) such as aluminium alloy or plastics, e.g., Perspex, formedby machining, moulding or other shaping process to produce a centralconical or exponentially shaped port (70), a mounting rim (68), fillingports (74) and a recessed groove (76). A vibrator element (54), such asthose manufactured by Kyocera and Murata for audio sounders, is attachedto the disc (52) around the mounting rim (68) by adhesive or bondingtechniques. The vibrator element (54) comprises a brass disc electrode(53) about 0.2 m thick and 20 mm diameter onto which is bonded a smallerdisc of piezo-electric material (56). One or more electrodes (58) and(60) are formed on the piezo-electric material (56) and lead wires (62)are connected to these electrodes and to disc electrode (53). When anelectric field is applied between the electrodes, the vibrator elementbends and may be excited into mechanical resonance by application of analternating voltage at appropriate frequency. An array of nozzles (50)is attached over the narrow opening of the port (70) by adhesive orother bonding technique. The groove (76) prevents excessive spreading ofadhesive over the disc surface where a cap may need to seal. The liquidto be ejected is introduced into the cavity formed by the disc (52),vibrator element (54) and nozzle array (50) by one or more feed tubes(64), sealed into the filling ports (74). When the vibrator element (54)is excited into a suitable resonance then ultrasonic vibrations aretransferred into the liquid (16) and around the rim of the vibratorelement into the disc (52) by motion of the vibrator element (54). Theseeffects result in ultrasonic pressure pulses within the liquid (16)behind the nozzle array (50) and droplets (72) are formed as the liquid(16) is periodically ejected through the nozzle array (50) at ultrasonicfrequencies. The optimum frequency of operation depends on theelectromechanical properties of the vibrator element and on the fluiddynamics through the nozzles. With nozzle diameters in the range 5 to 10μm, vibrator resonances in the range 100 to 250 kHz cause dropletemission from the device with modest electrical drive powers (<1 W). Theresonances employed correspond to complex modes of vibration of thevibrator element (54) and are one or two orders of magnitude above theaudible fundamental mode of vibration at which operation was intended bythe manufacturers.

The central portions of the vibrator element (54) exhibit the highestamplitude of operation and the resulting pressure waves in the liquid(16) are concentrated by the tapered port (70) onto the nozzle array(50). In one embodiment, the overall size of the aerosol generator isapproximately 20 mm in diameter and 3 mm thick. Efficient operation isobserved with a conical central port tapering from 3 mm diameter to a 1mm diameter droplet emitting area and a rim height of around 0.25 mm.Disc materials with both a low acoustic impedance and losscharacteristics at the ultrasonic frequencies employed, e.g. aluminiumalloy or Perspex were found to be the most suitable. If necessary allsurfaces in contact with the liquid (16) may be coated with a protectivelayer, e.g. electroplated Ni or anodised to prevent corrosion.

The nozzle array (50) may be fabricated from an electroformed metal ormetal alloy such as nickel or by anisotropic etching of a silicon wafer.FIGS. 5a and 5b depict a cross-section through part of a silicon nozzlearray and an electroformed nickel nozzle array respectively. It isimportant for the efficient operation of the device for the nozzle totaper in leading up to the nozzle exit. The silicon nozzles show alinear profile whereas the electroformed nozzles show a curved profile,however, both geometries work effectively. The silicon nozzles may befabricated by selective, anisotropic etching down the crystal planes ofa double sided polished <100> silicon wafer. The etched nozzles weredefined by photoresist and silicon oxide masks and etched in EDPsolution. Such techniques are familiar to those versed in the art ofsilicon microfabrication techniques and are often used for producingthin diaphragms for pressure sensors. In either case, typically nozzleexit sizes are 5 to 10 μm and the nozzle plate thickness is typicallyaround 20 to 100 μm.

The alternating voltage drive to the vibrator element (54) must bemaintained at the correct frequency and amplitude to most efficientlyexcite the required resonance mode. It is common for audio vibratorelements to include a feedback electrode on the piezo layer whichdevelops a potential when the vibrator element is flexed. Thus, theamplitude or phase or both of the signal from the feedback electroderelative to an oscillating drive signal voltage may be used to infer themechanical behaviour of the vibrator element. Such a scheme is oftenused in the audio drive circuits for these vibrator elements. It is anaspect of this invention that the signal from a conventional audiofeedback electrode may be used to control the drive electronicsoperating at ultrasonic frequencies, by locking the drive oscillator toa selected resonant mode. Manufacturing tolerances and the change invibrator element (54) electromechanical properties when bonded to a disc(52) and placed in contact with a liquid (16) preclude accurateprediction of the required resonant frequency. The resonant peak maytypically only be estimated to fall within a 10 to 20 kHz bandwidth.

With reference to FIG. 6a, a scheme for driving the vibrator element ofthe aerosol generator (84) at the correct frequency is illustrated by afunctional block diagram. The vibrator element (54) is driven by avoltage controlled oscillator (VCO) (80) via a power output stage (82).The upper and lower frequency bounds of the VCO (80) may be preciselyset to span a frequency range within which only the required resonancepeak will lie. When the circuit is first energised the VCO (80) drivesthe vibrator element at the lower end of the frequency band. Theamplitude of the signal from the vibrator element feedback electrode isderived by an envelope detector (demodulator) (86) and is comparedagainst a preset threshold by the amplitude comparator (90). If thepreset amplitude threshold is not exceeded i.e., the feedback signal isweak, then a ramp generator (92) continuously outputs a triangularvoltage waveform against time to the VCO (80). As a result of this, theVCO (80) output frequency and hence the drive frequency to the vibratorelement (84) is continually swept up and down between the fixedfrequency bands of the VCO (80). If the feedback signal amplitudeexceeds the preset threshold, i.e., the feedback signal is strongerindicating close proximity to the resonance peak, then an amplitudedifferentiator and comparator in (88) is used to determine whether thefeedback signal is increasing or decreasing in magnitude. If it is foundto be increasing then the voltage ramp direction remains unchanged, ifit is steady or decreasing then the ramp direction is reversed. Withthis arrangement, a resonance peak is first located and then locked toby continuous `hunting` about the peak response frequency.

With reference to FIG. 6b, a similar but simpler scheme for driving thevibrator element is described. Its mode of operation is similar to thatof the system illustrated in FIG. 6a except that the amplitude thresholdcomparison is not made, but instead the signal amplitude is taken to behigh enough all of the time, i.e., the frequency is always assumed to bein the vicinity of the required resonance peak. This latter system ispreferable because of its reduced complexity but, it does require theresonant frequency to be more accurately predicted than is necessary forthe former system described in FIG. 6a.

FIGS. 7a-7f show some example electronic circuits which may comprise thefunctional blocks illustrated in FIGS. 6a and 6b. The demodulator (86)comprises capacitors (700 and 703), diodes (701 and 702), resistor (704)and operational amplifier (op amp) (705). The alternating voltage signalfrom the vibrator element feedback element is input to the a.c. coupleddemodulator (86) which gives a d.c. analogue output related to inputsignal amplitude. The amplitude comparator (90) comprises resistors (707and 708), potentiometer (706) and comparator (709). If the signal from(86) exceeds the threshold set by (706) then the output signal level to(92) is `high`. The comparator hysteresis is set by (707 and 708).

The amplitude differentiator and comparator (88) comprises resistors(710, 712,713, 716, 717, 718, 719 and 720), capacitors (711 and 715),operational amplifier (714) and comparator (721). The op-amp (714) andits associated components differentiate the amplitude signal from (86).The amplitude derivative is then thresholded by the comparator (721) andits associated components such that the output to (92) is `low` when thesignal from (86) is rising.

The ramp generator (92) comprises logic gates (722, 723, 724, 725, 726,727, 728, 729 and 730), resistors (731, 732, 733,734 and 735), capacitor(736) and comparator (737). If the input level from (90) is `low` thenthe output voltage to (80) will be a continuous triangular waveformoscillation. If the input level from (90) is `high` then the outputvoltage to (80) will be a ramp waveform, which changes directionwhenever the input level from (88) goes `high`. If the latter remains`low` then the ramp direction, whether it be up or down, remainsunchanged.

The ramp voltage from (92) controls the VCO circuit (80) which comprisesa VCO IC (741) together with resistors (738 and 739) and capacitor (740)which determine the upper and lower frequency limits of the VCO.

The output stages (82) comprise n-channel MOSFETS (742 and 743),resistors (748, 749 and 750), transistors (744, 745, 746 and 747),diodes (753 and 754), capacitors (751 and 752), inductor (755) and logicgate (756). Components (742, 748, 744,745, 751, 753,754 and 752) form avoltage doubler circuit to increase the supply voltage available todrive the vibrator element. components (756, 743,749, 746, 747,755 and750) comprise a half bridge square drive circuit for the vibratorelement. The inductor (755) and resistor (750) in combination with thevibrator element provide a matching output drive filter which affectsthe amplitude and frequency content of the vibrator element drivewaveform, such that these may be set for optimum efficient operation.

With reference to FIG. 8, a breath actuation sensor comprises a pair offlap valves (110) and (106) covering apertures (130) and (132)respectively in a sheet of material (118). Behind flap valve (106) athermistor (102) is situated in an inlet port (126). The sheet (118) issecured into a manifold (100) by a screw (120). Aperture (122) of themanifold (100) leads to a mouth piece whereas aperture (124) of themanifold (100) is open to atmosphere. As the patient inhales through themanifold, flap valve (106) opens to position (108) and air is drawnthrough the port (126) past the thermistor (102). The air flow isdetected by its increased cooling effect on the thermistor (102) whichis maintained at a temperature some 100° C. or so above ambient by thepassage of an electrical current through it. The cooling effect on thethermistor is apparent by a change in the electrical resistance of thethermistor or by the electrical current required to maintain it at aconstant temperature and resistance. Such techniques are well known tothose versed in the art of `hot wire` type anemometers. The flap valves(106) and (110) ensure that the predominant air flow (114) over thethermistor (102) is due to inhalation rather than expiration. Suitableelectronics connected to the thermistor (102) can therefore generate asignal to trigger the aerosol delivery system when inhalation occursthrough the manifold aperture (122). A second port (128) and thermistor(104) may be included if the exhaled air flow (116) is to be monitored.During expiration the flap valve (106) remains closed and the flap valve(110) assumes position (112) thus directing the air flow predominantlyover thermistor (104).

With reference to FIG. 9, a sealing cap and reservoir vent valveassembly comprises a moveable member (150) onto which is attached a leafspring (140) which carries a cap body (142). The cap body (142) sealsagainst the front surface of the aerosol generator disc (52) outside ofthe groove (76) with a polymer `o` ring (144). Just before the `o` ring(144) seals the cap, a compliant polymer pad (146) contacts the nozzlearray (50) and is held against it by a small spring (148). The purposeof the pad (146) is to effect a good mechanical seal against the nozzlearray (50) which prevents air from being pushed in through the nozzlewhen the device is subjected to mechanical shocks. However, since theliquid (16) can be drawn by capillary action between the pad (146) andthe nozzle array (50) to the edges of the pad (146), an outer `o` ringseal (144) is also required to reduce evaporation losses from thesystem.

The vent port (18) from the reservoir is linked by tubing (24) and hole(154) to a vent valve comprising a compliant sealing ring (152) attachedto the member (150) and the surface of the leaf spring (140). Thisarrangement is such that when a force on the member (150) is applied toseal the cap against the aerosol generator, the leaf spring (140)contacts the sealing ring (152) to close the vent valve. Hence, theentire system is then sealed off from the atmosphere and may besubjected to mechanical shocks and handling without bubbles being drawninto the system. It can, however, be advantageous to allow a small leakto atmosphere to occur in the vent tube (24) or seal between (140) and(152) such that the system internal pressure can equilibrate toatmosphere when changes in ambient temperature or pressure occur.

With reference to FIG. 10, a configuration of a complete electronicmetered dose aerosol delivery system is illustrated by a function blockdiagram. Upon receiving a trigger signal from a manual start switch(180) or a breath actuation sensor (182), a cycle timer (176) is startedand a reset pulse generator (178) activated. The reset pulse isamplified by a power output stage (172) and sent to the liquid dosegauge (168). The reset pulse generator (178) and cycle time (176)signals are input to control logic circuits (162) which energise thevibrator element drive electronics (174) when the reset pulse hasfinished but the cycle timer is still running. With the cap (184)removed from the aerosol generator (170) and the reservoir (166) ventvalve (186) open, liquid flows from the reservoir (166) through thedosage gauge (168) and aerosol generator (170) when the vibrator elementdrive electronics (174) are energised. When the dose gauge (168) hasreached its end point, a `completed dose` signal is sent by the dosegauge electronics (164) to the control logic (162) which thendeactivates the vibrator element drive electronics (174). Provided thisoccurs before the cycle timer (176) has timed out then the correct dosewill have been delivered. If however, the `completed dose` signal is notreceived before the cycle timer (176) times out then the control logic(162) generates an alarm signal indicating a failed dose delivery. Thisalarm signal activates an audio or visual alarm (160). One such possibleaudible alarm is to drive the vibrator element (54) with an audiofrequency.

FIG. 11 shows a schematic diagram of an inhaler in accordance with theinvention comprising a housing (204) defining a chamber for the aerosolgenerator (210) which is in communication with a mouthpiece (208). Themedicament is held in reservoir (212) and may pass through conduits viadosage gauge (214) to the aerosol generator (210). Inhalation throughthe mouthpiece causes air flow through the air inlet (218), over thebreath sensor and flap valve (216) and past the aerosol generator to themouthpiece. On detection of the patient's inspiration a signal isreceived by the electronic control means (206) which activates theaerosol generator causing atomised droplets of liquid, represented byarrows (220) to be emitted into the air flow. The device is powered bybattery (202). (A mouthpiece cap, vent valves and wiring have beenomitted in the interests of clarity).

FIG. 12 is a schematic diagram of an electromechanical closure systemcombined with a droplet air mixer venturi in an inhaler having anaerosol generator of the type shown in FIGS. 4a and 4b. The aerosolgenerator (500) emits droplets into the throat of a venturi (502). Theair flow through the venturi (502) throat is at right angles to thedroplet emission direction and thorough mixing occurs before the exitflow (512).

The nozzle cover (504) is attached to a carrier (506) which has aninternal thread (510). The carrier (506) and cover (504) are movedlinearly by a leadscrew (508), which matches the thread (510), and amotor (516). The motor (516) is driven by a bipolar electrical supply(514) which can reverse the motor direction to move the cover on or off.When the cover is removed the carrier rests in the position (520)against a mechanical stop (518) marked in FIG. 12 with the cover flushwith the venturi throat wall, allowing the air flow to be almostundisturbed.

FIG. 13 represents an alternative liquid dose gauge to that shown inFIG. 3.

The liquid dose gauge comprises a tube or channel (418) containing ameasurement slug (424) with approximately neutral buoyancy in the liquid(416). At the start of the measurement cycle, the measurement slug (424)is reset against an end stop (422) by means of a magnetic slug (406) anda moving external magnet or magnetic field (not shown). The magneticslug (406) is then returned against the end stop (420). A light source(408) such as a light emitting diode projects light through a pair ofapertures (412 and 414) onto a photodiode (410). As the liquid (416)flows through the device, the measurement slug (424) moves along toposition (425) whereupon the slug (424) blocks out about half of thelight passing through the apertures (412 and 414) onto the photodiode(410). Electronics connected to the photodiode (410) detects thisoptical signal change and indicates that the liquid (416) dose has beendelivered.

With reference to FIGS. 14a-14c, electronic circuits to interface to thedose gauge of FIG. 13 are illustrated. The light emitting diode (LED)(408) is driven by oscillator components (902, 904, 906 and 908) anddriver components (910 and 912). The drive frequency is typically around1 to 10 kHz and enables the optical receiver to distinguish the signalfrom any background light.

Photodiode (410) is connected to a transimpedance amplifier circuit (918and 920) and is a.c. coupled to pass the modulation into an amplifiercircuit (922, 924, 926, 928 and 930). Point A therefore carries anamplitude modulated signal. When the measurement slug (424) in FIG. 13does not obscure the apertures (412 and 414) then a steady state a.c.signal is present at point A. A demodulation circuit with a timeconstant of around 0.1 to 1 second (932, 936, 940, 944, 948, 954 and956) generates a d.c. voltage at point B related to the signalamplitude. A second parallel demodulator circuit with a shorter timeconstant of around 1 to 10 milliseconds (934, 938, 942, 946, 950, 952and 958) generates a d.c. voltage at point C. The voltage at point B ispotentially divided by a factor of around 2 and compared to the voltageon point C by a comparator circuit (962, 960 and 964). State indicationof the comparator is achieved by driving an LED (968) through a resistor(966). In the steady state with light passing across the gauge, thecomparator drives the LED (968) on. When the apertures (412) and (414)shown in FIG. 13 are partially obscured, i.e., about half-way across, bythe slug (424) as it moves, then the transient change in signalamplitude at point A is followed by the faster demodulator (but not bythe slower one). Hence, the voltage at point C dips below that at pointD (which is about half that at point B) and the comparator statechanges, extinguishing the drive to the LED (968). Hysteresis providedby resistors (954, 956 and 960) maintains the comparator state until theoptical signal magnitude increases when the slug (424) is reset.

FIGS. 15 to 19 illustrate an inhaler in accordance with the inventionhaving a reusable hand unit and replaceable cartridge.

FIGS. 15a, b and c represent end side and plan views showing thecomponents of the inhaler with the cartridge in place. The inhalercomprises a housing (600) having a mouthpiece (602) and air inlet ports(604). The housing contains a replaceable cartridge, details of whichare shown in FIGS. 16 and 17, comprising a reservoir (606) an aerosolgenerator (608) and dose gauge (610). As seen in FIGS. 16 and 17,reservoir (606), aerosol generator (608), and dose gauge (610), areformed as a single integral unit. In addition, as seen for example inFIG. 17, a continuous passageway is formed between reservoir (606) andaerosol generator (608) so as to allow for a continuous stream of liquidmedicament between the reservoir and the aerosol generator. The housingalso encloses the reusable components of the inhaler including the motor(612), the cap (614) for the aerosol generator and the venturi (616).

The aerosol generator (608) is shown in detail in FIGS. 16, 17 and 18.The generator comprises a housing (618) defining a chamber (620) havingat one end a nozzle array (622). The chamber is in communication with areservoir (606) via a dosage gauge (610). A vibrator element comprisinga piezo-electric ring (624) mounted on a metal disc (626) is attached inclose proximity to the nozzle array (622) such that ultrasonic energyfrom the vibrator element is transferred directly to the nozzle array.The metal disc (626) is shaped (see FIG. 18) such that it may beaccommodated in the curve of the venturi (616) (see FIG. 15b). Thediameter of the metal disc is preferably about 20 mm and it is attachedover a central portion of about 4 mm diameter. The vibrator element ispreferably driven at high frequency e.g. 250 to 400 kHz to provide agood flow rate through the aerosol generator and to reduce the effect ofbubble formation.

The aerosol generator is sealed by a cap (614) when not in use (see FIG.15a). The cap is carried on a slider which is moved by a lead screw(630) driven by motor (612). The motor (612) is mounted on a block (613)secured to base plate (615). When the inhaler is switched on by switch(618) the motor is activated causing the slider (628) to be moveddisplacing the cap (614) away from the aerosol generator (608) as shownin FIG. 19 and in dotted outline in FIG. 15a.

The dosage gauge (610) is positioned between the reservoir (606) and theaerosol generator (608). The reservoir (606) comprises a sachet which isheat sealed around its margins and comprises a connector (632) toprovide a liquid communication with the dose gauge (610). The dose gaugecomprises a tube (634) containing a neutral buoyancy measurement slug(636), a magnetic reset slug (638) an upstream end stop (640) and adownstream stop (642). The detection means for the slug (636) comprisesa light emitting diode (644) and a photodiode (646). The slug (636) isconveniently provided with a shaped end (648) e.g. hemispherical, whichmay be held in sealing engagement with a corresponding shaped surface(650) at the end of the upstream stop (640) to provide a valvepreventing liquid flow. The slug (636) is held against the stop (640) bymoving the magnetic slug (638) upstream and holding the magnetic slug inthat position. Movement of the magnetic slug (638) is accomplished bymagnet (652) mounted on the slider (628) of the cap. Thus, when the cap(614) is in the closed position the magnetic slug (638) will be moved toits upstream position holding the slug (636) against the upstream stop(640), thereby acting as a closed valve. When the cap (614) is moved toits opened position the magnet (652) will be moved with the slider (628)causing movement of the magnetic slug to its downstream position,thereby allowing movement of the slug (636) when the aerosol generatoris operated. Operation of the aerosol generator causes dispensing of theliquid medicament and movement of the slug (636) downstream to bedetected by the detection system comprising the light emitting diode andphoto-diode. The detection system may be of the digital type i.e.providing dose not completed and dose completed outputs only to switchoff the aerosol generator when a dose has been administered, or it canbe of the analogue type to give a continuous reading of volume dispensedfrom which the instantaneous flow rate can be derived for frequencytuning of the aerosol generator. For example, the frequency scanningreferred to with respect to FIG. 6a could be used to locate a vibratorelement drive frequency which gives a flow rate exceeding apre-determined flow rate threshold. The analogue dose gauge may utilisea larger area light source and detector such that the received signalwill vary according to the position of the slug (636).

The venturi (616) performs the function of mixing the liquid dropletsemitted by the aerosol generator with an orthogonal air stream beforethe droplets have a chance to collide with each other too many times.The droplet size is very important in the delivery of drug to therespiratory system of the patient and repeated collision of droplets canresult in the formation of large droplets which are too large to beinhaled properly. As the patient breathes through the mouthpiece (602)air passes through the inlet holes (604) in the housing and throughinlet port (654) (FIG. 15b) into the venturi. A thermistor (656) ispositioned within the port (654) to detect the incoming air flow andprovide a signal which actuates the aerosol generator. The incoming airto the venturi is distributed over the whole venturi inlet by theprovision of air buffer space (658) and foam disc (660) which is an opencell foam providing some resistance to the incoming air flow so that theair flow from the foam pad is substantially the same in all regions andis independent of the turbulence of the incoming airstream. Air from thefoam buffer passes through a honeycomb of tubes (662) to remove anytranslational turbulence in the airstream and to ensure the air flowacross the nozzle array is laminer. The tubes preferably have aninternal diameter of 0.5 to 1 mm and a length of about 5 mm. Thehoneycomb may conveniently be constructed from corrugated foil coiledinto a spiral. The air flow from the honeycomb tubes is an even laminarflow and the venturi gradually closes down increasing the air velocityfor mixing with the droplets from the aerosol generator at the venturithroat. Thereafter, the venturi expands and the velocity of the air flowand entrained droplets is reduced before reaching the mouthpiece. Inorder to maintain a slight negative pressure in the reservoir it may bedesirable to provide a conduit or passage connecting the venturi to theregion of the reservoir in view of the low pressure in the venturiduring inhalation.

It is not essential for the vibrating element to be present in thereplaceable cartridge and it is possible to incorporate this componentinto the re-usable unit. FIG. 20 of the accompanying drawingsillustrates different configurations by which a nozzle array (FIG. 20a)may be located within a vibrating element (FIGS. 20b, c and d) to forman aerosol generator.

FIG. 20a shows a nozzle array (700) positioned at the end of a straightsection tube (702) which forms the tube of a dosage gauge and cavity.The dose gauge end stop (704) and a portion of the magnetic slug (706)are shown. Different configurations of vibrating element comprising apiezo-electric ring (708) and metal disc (710) are shown in FIGS. 20b, cand d. The arrangements of FIGS. 20b and c differ in the position of thepiezo-electric ring (708). FIG. 20d illustrates a shaped metal disc(710) which facilitates fitment into the throat of the venturi (712).

It has been found that efficient aerosol generation is achieved if thenozzle arrangement and vibrating element are constructed and arranged toensure radial transfer of energy. Thus, it is preferred that the nozzlearray (700) and/or tube (702) is a tight fit within the disc (710) inorder to optimise the transfer of ultrasonic energy between thevibrating element and nozzle array. This may be achieved by thearrangement as illustrated in FIG. 20, although other configurations arereadily possible, for example, the end of the tube (702) may be providedwith a conical surface which fits within a complementary aperture on themetal disc.

The aerosol generator may comprise means other than a piezo-electricelement to generate the necessary vibrations. The emergence ofmagnetostrictive materials, such as, Terfenol D in recent years allowsthe use of such materials as a driving element. Whilst the present costof these materials is higher than that of piezo-electric elements, theenergy density is higher and equivalent power actuators can be made withless material. Such actuators are electro-magnetically excited and thecoil turns may be tailored to suit a given drive voltage such as thebattery voltage, without need for additional inductors or transformerswhich the higher voltage piezo-electric elements may require.

FIG. 21 of the accompanying drawings illustrates a nozzle arrangementhaving a magnetostrictive actuating element. The arrangement comprises amagnetorestrictive tube (720) magnetically biased by a permanent magnet(722) and excited by windings (724) forming an electro magnet. The polepieces (726, 728) confine the flux within the tube (720). An alternatingcurrent in the windings (724) induces an alternating flux in themagnetorestrictive tube (720) which causes it to change its length.Thus, pole piece (728) moves in an oscillating manner with respect tothe magnet (722). A tube and nozzle array as illustrated in FIG. 20a maybe pushed into the magnetostrictive tube (720) such that the nozzlearray is pushed against the face (730) of the pole piece (728) so thatvibrations from the motion of pole piece (728) are transferred to thenozzle array.

We claim:
 1. An inhaler device for dispensing droplets of liquidmedicament to a patient comprising a body having a mouthpiece or nasaladaptor, a reservoir of liquid medicament, and an aerosol generator incommunication with said reservoir, the aerosol generator comprising achamber for liquid medicament and a nozzle arrangement comprising aplurality of orifices in fluid flow relationship with liquid medicamentin said chamber, the reservoir having walls which tend to spring to astate of maximum internal volume so as to create a slight negative headof pressure within said reservoir and said chamber, the aerosolgenerator further comprising means for cyclically pressurising theliquid medicament in said chamber such that liquid from said chamber isperiodically expelled through the orifices as atomised droplets ofliquid medicament so they may be inhaled via the mouthpiece or nasaladaptor, the inhaler device additionally comprising dosage control meansfor deactivating the aerosol generator after a predetermined time orafter a predetermined volume of liquid medicament has been expelled fromthe chamber.
 2. An inhaler device as claimed in claim 1 wherein themeans for cyclically pressurising the liquid medicament comprises a wallopposite the nozzle arrangement comprising a flexible portion attachedto a piezo-electric element such that excitation of the piezo-electricelement causes vibration of the flexible portion resulting in cyclicpressurisation of the liquid medicament in the chamber.
 3. An inhalerdevice as claimed in claim 2 comprising means to excite thepiezo-electric element at a resonant frequency within the frequencyrange of about 10 to 500 kHz.
 4. An inhaler device as claimed in claim 2further comprising means to excite the piezo-electric element at aresonant frequency within the frequency range of about 100 to 250 kHz.5. An inhaler device as claimed in claim 2 further comprising means toexcite the piezo-electric element at a resonant frequency within thefrequency range of about 50 to 250 kHz.
 6. An inhaler device as claimedin claim 1 wherein the nozzle arrangement is flexible and the means forcyclically pressurising the liquid medicament comprises a piezo-electricelement associated with the flexible nozzle arrangement such thatexcitation of the piezo-electric element causes vibration of the nozzlearrangement resulting in cyclic pressurisation of the liquid medicamentin the chamber.
 7. An inhaler device as claimed in claim 6 wherein thepiezo-electric element is in the form off a ring secured to a metaldisc, the ring and metal disc each having a central opening toaccommodate attachment of the piezo-electric element to the aerosolgenerator adjacent the nozzle arrangement.
 8. An inhaler device asclaimed in claim 7 further comprising means to excite the piezo-electricelement at a resonant frequency within the frequency range of about 250to 400 kHz.
 9. An inhaler device as claimed in claim 6 furthercomprising means to excite the piezo-electric element at a resonantfrequency within the frequency range of about 250 to 400 kHz.
 10. Aninhaler device as claimed in claim 1 wherein the reservoir is in theform of a collapsible bag.
 11. An inhaler device as claimed in claim 1wherein the dosage control means comprises means for measuring thevolume of liquid supplied to the chamber, means for generating a signalafter a predetermined volume of liquid has been measured, and means fordeactivating the aerosol generator upon the generation of said signal.12. An inhaler device as claimed in claim 11 further comprising aconduit connecting the reservoir and the chamber, the volume measuringmeans comprising a close fitting, free moving slug positioned in saidconduit and having a density matched to that of the liquid medicamentand means for detecting the position of the slug comprising optical,mechanical, or electromagnetic detection means.
 13. An inhaler device asclaimed in claim 12 in which the volume measuring means additionallycomprises two stops for limiting movement of the slug therebetween andmeans for setting the slug against the upstream stop.
 14. An inhalerdevice as claimed in claim 12 wherein the detecting means comprisesmeans for continuously detecting the position of the slug and saidsignal generating means is capable of providing a signal representativeof the instantaneous flow rate.
 15. An inhaler device as claimed inclaim 14 wherein said means for cyclically pressurising the liquidmedicament comprises a piezo-electric element which vibrates saidaerosol generator when excited, said inhaler device further comprisingmeans for modulating the excitation of said piezo-electric element inaccordance with said signal.
 16. An inhaler device as claimed in claim 1further comprising a breath actuation sensor for detecting a patient'sinspiration through the mouthpiece or nasal adaptor and means foractuating the aerosol generator when inspiration is detected.
 17. Aninhaler device as claimed in claim 16 in which the breath actuationsensor comprises a pivoted vane, a flow transducer, a pressuredifferential transducer or a temperature sensor.
 18. An inhaler deviceas claimed in claim 1 further comprising means for removing gas bubblesfrom the liquid medicament comprising a microporous material having onesurface in contact with the liquid medicament and an opposite surfaceexposed to a region of low pressure or vacuum.
 19. An inhaler device asclaimed in claim 1 further comprising a venturi in communication withthe mouthpiece or nasal adaptor such that the atomized droplets aredirected into and substantially at right angles to the air flowgenerated through the venturi during inhalation through the mouthpieceor nasal adaptor.
 20. An inhaler device as claimed in claim 1 whereinthe inhaler device is configured as a reusable hand unit with areplaceable cartridge, said replaceable cartridge including the aerosolgenerator, including the nozzle arrangement and the chamber, and thereservoir as a single integral unit, a continuous passageway beingformed between said reservoir and said aerosol generator so as to allowfor a continuous stream of liquid medicament between said reservoir andsaid aerosol generator.
 21. An inhaler device for dispensing droplets ofliquid medicament to a patient comprising a body having a mouthpiece ornasal adaptor, a reservoir of liquid medicament, and an aerosolgenerator in communication with said reservoir, the aerosol generatorcomprising a chamber for liquid medicament and a nozzle arrangementcomprising a plurality of orifices in fluid flow relationship withliquid medicament in said chamber, the aerosol generator furthercomprising means for cyclically pressurising the liquid medicament insaid chamber such that liquid from said chamber is periodically expelledthrough the orifices as atomised droplets of liquid medicament so theymay be inhaled via the mouthpiece or nasal adaptor, the inhaler deviceadditionally comprising dosage control means for deactivating theaerosol generator after a predetermined time or after a predeterminedvolume of liquid medicament has been expelled from the chamber, theinhaler device further comprising means for removing gas bubbles fromthe liquid medicament comprising a microporous material having onesurface in contact with the liquid medicament and an opposite surfaceexposed to a region of low pressure or vacuum.
 22. An inhaler device asclaimed in claim 21 wherein the inhaler device is configured as areusable hand unit with a replaceable cartridge, said replaceablecartridge including the aerosol generator, including the nozzlearrangement and the chamber, and the reservoir as a single integralunit, a continuous passageway being formed between said reservoir andsaid aerosol generator so as to allow for a continuous stream of liquidmedicament between said reservoir and said aerosol generator.
 23. Aninhaler device as claimed in claim 21 wherein the nozzle arrangement isflexible and the means for cyclically pressurising the liquid medicamentcomprises a piezo-electric element associated with the flexible nozzlearrangement such that excitation of the piezo-electric element causesvibration of the nozzle arrangement resulting in cyclic pressurisationof the liquid medicament in the chamber.
 24. An inhaler device asclaimed in claim 23 wherein the piezo-electric element is in the form ofa ring secured to a metal disc, the ring and metal disc each having acentral opening to accommodate attachment of the piezo-electric elementto the aerosol generator adjacent the nozzle arrangement.